In his new incarnation, the Doctor draws back from continuous involvement with UNIT (with which he had worked closely as the Third Doctor) and the Time Lords. The Time Lords continue to send him on occasional missions, including an attempt to prevent the creation of the Daleks, during which he also meets a new adversary, Davros. The Doctor travels with journalist Sarah Jane Smith, whom he had befriended prior to his regeneration, and, for a time, with UNIT Surgeon-Lieutenant Harry Sullivan.

The Doctor's companionship with Sarah Jane is ended when he receives a telepathic summons to Gallifrey, as humans were not then allowed on the planet. The summons is part of a trap set by his enemy the Master, who has used up all his regenerations and become little more than a withered husk. The Master frames the Doctor for the assassination of the President of the High Council of Time Lords. In order to avoid execution, the Doctor invokes an obscure law and declares himself a candidate for the office, giving himself the time he needs to defeat the Master.

The Doctor is seen to travel alone for the first time since season 1, returning to a planet he had visited centuries before. During his previous visit, he had accidentally imprinted a human colony ship's powerful computer, Xoanon, with his own mind, leaving it with multiple personalities. On his second visit the Doctor is remembered as an evil god by the descendants of the colonists, some of whom had become a warrior tribe called the Sevateem. After the Doctor cures the computer, one of the Sevateem, Leela, joins him on his travels. The Doctor brings the intelligent but uneducated Leela to many locales in human history, teaching her about science and her own species' past. In Victorian London, the pair encounters the magician Li Hsien Chang and his master, the self-styled Weng-Chiang. Later, the Doctor and Leela visit the Bi-Al Foundation medical centre, where they acquire the robot dog K-9.

The Doctor returns to Gallifrey and declared himself Lord President, based on the election held during his previous visit. This is a ploy to reveal and defeat a Sontaran invasion plan. Leela and K-9 decide to remain on Gallifrey; the Doctor comforts himself by producing K-9 Mark II.

Shortly afterwards, the powerful White Guardian assigns the Doctor to find the six segments of the Key to Time, sending a young Time Lady named Romana to assist him. The two Gallifreyans find the six segments and defeat the equally powerful Black Guardian, who sought the Key for himself. After the conclusion of the quest, Romana regenerates into a new form.

For a time, the Fourth Doctor and the second incarnation of Romana travel in another universe known as E-Space. There, they are joined by the young prodigy Adric. When the Doctor finds a way to leave E-Space, Romana and K-9 Mark II choose to remain behind. Adric and the Doctor are joined by the aristocratic orphan Nyssa of Traken and, in the Fourth Doctor's last adventure, by the opinionated Tegan Jovanka.

The conduit between E-Space and our own universe is revealed to be a Charged Vacuum Emboitment (CVE) — created by the mathematicians of Logopolis as part of a system to allow the Universe to continue on past its point of heat death. As he investigates this, the Fourth Doctor begins experiencing ominous feelings and spots a white-clad entity, "The Watcher," observing him. After succeeding in stopping the Master from disrupting the CVEs and destroying the universe, the Fourth Doctor is mortally wounded when he falls from the Pharos Project radio telescope control tower, where he utters his last words: "It's the end -- but the moment has been prepared for." The Watcher is revealed as a manifestation of the Doctor's future incarnation. Before the eyes of the Doctor's companions, the Watcher merges with the Fourth Doctor, regenerating him into the The 10th Doctor and as a wife named Taylor Swift

The Fourth Doctor appears once more in the 20th anniversary special The Five Doctors. A renegade Time Lord attempts to pull the first five incarnations of the Doctor out of time, inadvertently trapping the Fourth Doctor (and Romana) in a "time eddy" from which they are later freed. Brief holographic clips of the Fourth Doctor appear in "The Next Doctor" and "The Eleventh Hour".